Our long-term goal is to understand the biological significance and evolutionary implications of contrasting levels of DNA sequence polymorphism within and between species. Of particular interest are the frequency and nature of variants with functional consequences that are the targets of adaptive evolution. We are interested in the evolutionary forces shaping specific genes, and in the determinants of genome-wide patterns of variation and molecular evolution as they are influenced by variation in rates of recombination. We propose completing single and multi-gene analyses aimed at inferring the distribution of selective effects acting on synonymous, non-synonymous, and intron sequence variants within and between Drosophila melanogaster and D. simulans. Sequence polymorphism data will be generated in order to test hypotheses concerning the efficacy and direction of selection acting on different classes of sequence variants. Our primary focus will also shift to an extension of our microsatellite-based genome scan for adaptive fixations, focusing on a 2 Mb high-recombination region on the X chromosome of D. melanogaster and D. simulans. Evidence for selective sweeps will be verified and the targets of these selective sweeps localized within the genome using a finer resolution, DNA sequence polymorphism scan. These data will allow estimation of the timing, strength, and target of selection. Finally, we will carry out a molecular characterization of the genes and associated variation at identified targets of selection. Our proposed research will make significant contributions to our understanding of the processes by which genomes evolve and organisms adapt to their environments. It will also contribute to gene annotation efforts, continue to serve as empirical motivation for new theoretical studies and statistical tests, and will provide a conceptual framework in which to interpret DNA polymorphism data increasingly available from other organisms including humans.